DESCRIPTION: Thyroid hormone (T3) and its two receptors (TRa and TR ) are essential for the development of the auditory system. This proposal will correlate specific cellular and physiological processes in auditory development with defined transcriptional pathways from a given TR variant to its downstream target genes to determine the extent to which TRa and TR mediate unique or uncooperative functions. The auditory defect in TR-deficient mice will be investigated morphologically and functionally, focusing on the cochlea as the primary T3-sensitive site in the auditory system. These studies are designed to enhance our understanding of the role of T3 and TR genes in auditory development and function. These specific aims as listed in the proposal are: (1) To investigate the cellular and physiological functions of TR in cochlear development; (2) To investigate the function and expression of TR 2 in the cochlea by targeted mutagenesis of a TR 2-specific exon; (3) To determine the individual and combined functions of TR and TR[alpha]; (4) To investigate ligand availability in the developing cochlea; (5) To investigate TR-dependent transcriptional pathways (to isolate and characterize target genes).